Development of Asymmetric Cooperative Gold Catalysis and Beyond

协同催化或涉及金属-配体协同的催化是一种高度通用的方法， 催化，导致了无数的高效合成方法，并赋予了特殊的价值， 生物活性和/或药物化合物的化学合成。尽管在这方面取得了非凡的进展， 研究课题，仍然需要开发基于独特配体设计的新的合作系统， 使得能够开发新的和/或大大改进的化学合成方法。 2014年，PI启动了一项开发双官能联芳基-2-基膦配体的计划， 设计成能够进行协同金（I）催化。这些配体具有远程碱性基团， 在催化过程中与底物或试剂的键合相互作用，从而实现配体-金属配合。 一些初步的研究，包括ppm级的金催化的羧酸与炔的加成， 炔不对称异构化为丙二烯，以及催化生成的σ-丙二烯基金的捕获 中间体与醛的反应，验证了配体设计和催化的协同性质。 作为PI未来工作的主要重点，该提案寻求将这种合作金（I）催化应用于 战略发展的不对称转换的特殊综合价值观。这些包括 手性丁烯内酯和2，5-二取代吡咯啉的简便合成及不对称炔丙基化反应 反应/炔丙基C-H官能化。这种策略的扩展到更便宜的合作Cu（I） Ag（I）催化为不对称烯醇化物质子化提供了新的独特的机会， 获得各种羰基产物的宝贵途径。向官能化的N，N-二齿配体的转变将 使合作配体设计概念能够应用于更广泛的金属催化， 提供了以不对称方式操纵羰基化合物的前所未有的机会。 如果实施，该提议将引入一系列新的和通用的手性双官能配体， 金属催化和激发越来越多的研究努力在合作催化。此外，开发的方法 将提供对化学合成具有高价值的多种手性结构的有效途径， 尤其是医药研发。

Cooperative catalysis or catalysis involving metal-ligand cooperation is a highly versatile approach in catalysis that have resulted in a myriad of highly efficient synthetic methods and conferred exceptional value to chemical synthesis of bioactive and/or pharmaceutical compounds. Despite extraordinary advances on this research topic, there are still much need to develop new cooperative systems based on unique ligand designs to enable the development of new and/or much improved synthetic methods for chemical synthesis. In 2014, the PI initiated a program on the development of bifunctional biaryl-2-ylphosphine ligands that are designed to enable cooperative gold(I) catalysis. These ligands feature remote basic groups that can engage bonding interactions with substrates or reagents during catalysis and thereby achieve ligand-metal cooperation. Several preliminary studies, including a ppm-level gold-catalyzed addition of carboxylic acid to alkyne, an asymmetric isomerization of alkyne into allene, and trapping of catalytically generated σ-allenylgold intermediate with aldehyde, have validated the ligand design and the cooperative nature of the catalysis. As the major focus of the PI’s future effort, this proposal seeks to apply this cooperative gold(I) catalysis strategy to the development of asymmetric transformations of exceptional synthetic values. These include expedient construction of chiral butenolids and 2,5-disubstituted pyrrolines and asymmetric propargylation reactions/propargylic C-H functionalizations. The extension of this strategy to much cheaper cooperative Cu(I) and Ag(I) catalysis offers new and distinct opportunities in asymmetric enolate protonation, which would open valuable access to various carbonyl products. The transition to functionalized N,N-bidentate ligands would enable the application of the cooperative ligand design concept to a much broader range of metal catalysis and offer unprecedented opportunities to manipulate carbonyl compounds in asymmetric manners. This proposal, if implemented, would introduce a range of new and versatile chiral bifunctional ligands to metal catalysis and inspire increasing research effort in cooperative catalysis. Moreover, the methods developed would provide efficient access to a variety of chiral structures of high value to chemical synthesis in general and pharmaceutical R&D in particular.